The striatum is a key brain area that plays a central role in the initiation and execution of voluntary movements. Medium spiny neurons (MSNs) are the most common cell type in the striatum and they give rise to the inhibitory projections that striatum sends to other brain areas involved in motor coordination. Degeneration or perturbed function of MSNs occurs in several human movement disorders including Huntington's and Parkinson's as well as in certain psychiatric illnesses and drug addiction. Furthermore, perturbation of signaling by the neuromodulator dopamine is thought to contribute to both Parkinson's disease and drug addiction. However, because little is known about the functional properties of MSNs and about the actions of neuromodulators in the striatum, the processes that give rise to the neuropsychiatric symptoms of these diseases are poorly understood. The proposed work will use a combination of 2-photon laser scanning microscopy, 2-photon laser uncaging, and whole-cell electrophysiology to analyze how MSNs integrate the activity of many synapses and how this process is altered by neuromodulators. We will examine how neuromodulators alter the property of synapses formed onto MSNs as well as the intrinsic properties of MSNs. Furthermore, we will determine how the properties of the presynaptic terminal, of dendritic ion channels, and of glutamate receptors interact to determine synaptic responses in MSNs. Ultimately, we hope to understand how the specialized electrophysiological and morphological properties of MSNs influence striatal function and how perturbation of these processes contributes to human disease. PUBLIC HEALTH RELEVANCE: The properties and regulation of synapses in the striatum are poorly understood. In order to explain how perturbations of striatal function lead to human neuropsychiatric diseases, it is necessary to first obtain a detailed understanding of normal synapse and neuron function in this brain region. Our studies will provide a description of how striatum neurons integrate information and allow us to eventually determine how these processes are altered in human disease.